Our overall long-term goal is to develop methods to accurately measure subtle brain changes due to one of the most under-diagnosed injuries, mild traumatic brain injury. In the current project, we propose to study chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with prior exposure to repetitive head impacts (RHI), such as those incurred from contact sports. We plan to work with the Center for the Study of Traumatic Encephalopathy to perform sophisticated white matter tract analyses of neuroimaging data acquired as part of their R01 (Chronic Traumatic Encephalopathy: Clinical Presentation and Biomarkers, PI Robert Stern). The data includes a sample of retired National Football League (NFL) players who are believed to be at high risk of developing CTE and a sample of control athletes matched for age. This exciting project proposes to apply advanced diffusion magnetic resonance imaging (dMRI) analysis methods to the study of biomarkers of CTE. dMRI is sensitive to brain changes caused by mild traumatic brain injury (mTBI), but it is not yet known how best to detect these changes. Most prior work in dMRI analysis for mTBI has been limited to single tensor models (with shortcomings in regions of crossing white matter tracts) and measurement of basic diffusion indices such as fractional anisotropy (which suffers from non-specificity regarding possible underlying biological mechanisms). In contrast, we propose to evaluate single and more sophisticated multi-tensor models, using tract-based measurements we have developed and microstructure measures from multishell dMRI, and to empirically determine which diffusion indices are the most informative as potential biomarkers. We hypothesize that dMRI measures will provide a sensitive marker of white matter (WM) neurodegeneration. We propose to measure white matter changes by comparison to a model of the normal brain that we will construct from the control athlete data. The model will describe the diffusion indices along major white matter fiber tracts. We will compare individual subjects to this model to detect regions of abnormal diffusion. Experiments will be performed to select the best-performing indices (potential biomarkers), then those indices will be employed to describe and quantify pathological changes. This proposal is expected to help develop biomarkers for CTE and to explore the clinical presentation of this disease likely to affect athletes at all levels of play, as well as other members of our society, such as combat military personnel. Our approach has the potential to advance our understanding of mTBI and CTE, towards the long-term goal of providing better diagnostic and prognostic information in the clinic.